title: Enhanced atherosclerosis in TIPE2-deficient mice is associated with increased macrophage responses to oxidized low-density lipoprotein.
abstract: Atherosclerosis has been widely recognized as an inflammatory disease of the arterial wall in which macrophages play a major role. Yet, how macrophage-mediated pathology is regulated during atherosclerosis is poorly understood. TNF-α-induced protein 8-like 2 (TIPE2, also known as TNFAIP8L2) is highly expressed in resting macrophages and can negatively regulate inflammation through inhibiting immune receptor signaling. We report in this article that TIPE2 plays a crucial atheroprotective role likely by regulating macrophage responses to oxidized low-density lipoprotein (ox-LDL). TIPE2-deficient macrophages treated with ox-LDL produced more oxidative stress and proinflammatory cytokines, and exhibited heightened activation of the JNK, NF-κB, and p38 signaling pathways. As a consequence, TIPE2 deficiency in bone marrow-derived cells exacerbated atherosclerosis development in Ldlr(-/-) mice fed a high-fat diet. Importantly, ox-LDL markedly downregulated TIPE2 mRNA and protein levels in macrophages, suggesting that ox-LDL mediates atherosclerosis by TIPE2 inhibition. These results indicate that TIPE2 is a new inhibitor of atherosclerosis and a potential drug target for treating the disease.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, 250012 China;
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Lou
authors.forename: Suxia
authors.initials: S
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Guizhong
authors.initials: G
authors.lastname: Zhang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.forename: Mei
authors.initials: M
authors.lastname: Ni
authors.forename: Guipeng
authors.initials: G
authors.lastname: An
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.forename: Wenqian
authors.initials: W
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D012333:RNA, Messenger; D011973:Receptors, LDL; C529002:TIPE2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases